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Herein, we have investigated tRNA\u2010derived fragment (tRF) profiles in MM and precursor stages (smoldering MM\/sMM; monoclonal gammopathy of undetermined significance\/MGUS), aiming to unveil potential MM\u2010related tRFs in ameliorating MM prognosis and risk stratification. Small RNA\u2010seq was performed to profile tRFs in bone marrow CD138<jats:sup>+<\/jats:sup> plasma cells, revealing the significant deregulation of the mitochondrial internal tRF<jats:sup>HisGTG<\/jats:sup> (mt\u2010i\u2010tRF<jats:sup>HisGTG<\/jats:sup>) in MM versus sMM\/MGUS. The screening cohort of the study consisted of 147\u2009MM patients, and mt\u2010i\u2010tRF<jats:sup>HisGTG<\/jats:sup> levels were quantified by RT\u2010qPCR. Disease progression was assessed as clinical end\u2010point for survival analysis, while internal validation was performed by bootstrap and decision curve analyses. Screening cohort analysis highlighted the potent association of reduced mt\u2010i\u2010tRF<jats:sup>HisGTG<\/jats:sup> levels with patients' bone disease (<jats:italic>p<\/jats:italic>\u2009=\u20090.010), osteolysis (<jats:italic>p<\/jats:italic>\u2009=\u20090.023) and with significantly higher risk for short\u2010term disease progression following first\u2010line chemotherapy, independently of patients' clinical data (HR\u2009=\u20091.954; <jats:italic>p<\/jats:italic>\u2009=\u20090.036). Additionally, mt\u2010i\u2010tRF<jats:sup>HisGTG<\/jats:sup>\u2010fitted multivariate models led to superior risk stratification of MM patients' treatment outcome and prognosis compared to disease\u2010established markers. Notably, our study highlighted mt\u2010i\u2010tRF<jats:sup>HisGTG<\/jats:sup> loss as a powerful independent indicator of post\u2010treatment progression of MM patients, leading to superior risk stratification of patients' treatment outcome.<\/jats:p>","DOI":"10.1111\/bjh.19332","type":"journal-article","created":{"date-parts":[[2024,2,28]],"date-time":"2024-02-28T06:14:24Z","timestamp":1709100864000},"page":"1790-1800","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Small <scp>RNA<\/scp>\u2010seq and clinical evaluation of <scp>tRNA<\/scp>\u2010derived fragments in multiple myeloma: Loss of mitochondrial <scp>i\u2010tRF<sup>HisGTG<\/sup><\/scp> results in patients' poor treatment outcome"],"prefix":"10.1111","volume":"204","author":[{"given":"Konstantinos","family":"Soureas","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Biology National and Kapodistrian University of Athens  Athens Greece"},{"name":"Laboratory of Clinical Biochemistry\u2014Molecular Diagnostics, Second Department of Pediatrics, School of Medicine National and Kapodistrian University of Athens, \u201cP. &amp; A. Kyriakou\u201d Children's Hospital  Athens Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria\u2010Alexandra","family":"Papadimitriou","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Biology National and Kapodistrian University of Athens  Athens Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Panagiotis","family":"Malandrakis","sequence":"additional","affiliation":[{"name":"Department of Clinical Therapeutics, School of Medicine National and Kapodistrian University of Athens, Alexandra General Hospital  Athens Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aristea\u2010Maria","family":"Papanota","sequence":"additional","affiliation":[{"name":"Department of Clinical Therapeutics, School of Medicine National and Kapodistrian University of Athens, Alexandra General Hospital  Athens Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Panagiotis G.","family":"Adamopoulos","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Biology National and Kapodistrian University of Athens  Athens Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ioannis","family":"Ntanasis\u2010Stathopoulos","sequence":"additional","affiliation":[{"name":"Department of Clinical Therapeutics, School of Medicine National and Kapodistrian University of Athens, Alexandra General Hospital  Athens Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine\u2010Ivy","family":"Liacos","sequence":"additional","affiliation":[{"name":"Department of Clinical Therapeutics, School of Medicine National and Kapodistrian University of Athens, Alexandra General Hospital  Athens Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Gavriatopoulou","sequence":"additional","affiliation":[{"name":"Department of Clinical Therapeutics, School of Medicine National and Kapodistrian University of Athens, Alexandra General Hospital  Athens Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diamantis C.","family":"Sideris","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Biology National and Kapodistrian University of Athens  Athens Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Efstathios","family":"Kastritis","sequence":"additional","affiliation":[{"name":"Department of Clinical Therapeutics, School of Medicine National and Kapodistrian University of Athens, Alexandra General Hospital  Athens Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8990-3254","authenticated-orcid":false,"given":"Meletios\u2010Athanasios","family":"Dimopoulos","sequence":"additional","affiliation":[{"name":"Department of Clinical Therapeutics, School of Medicine National and Kapodistrian University of Athens, Alexandra General Hospital  Athens Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2427-4949","authenticated-orcid":false,"given":"Andreas","family":"Scorilas","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Biology National and Kapodistrian University of Athens  Athens Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5133-1422","authenticated-orcid":false,"given":"Evangelos","family":"Terpos","sequence":"additional","affiliation":[{"name":"Department of Clinical Therapeutics, School of Medicine National and Kapodistrian University of Athens, Alexandra General Hospital  Athens Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2135-9886","authenticated-orcid":false,"given":"Margaritis","family":"Avgeris","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Biology National and Kapodistrian University of Athens  Athens Greece"},{"name":"Laboratory of Clinical Biochemistry\u2014Molecular Diagnostics, Second Department of Pediatrics, School of Medicine National and Kapodistrian University of Athens, \u201cP. &amp; A. 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